Project Summary/Abstract Substance abuse (e.g. cocaine) evolved to hijack a system already in place to respond to natural, adaptive rewards such as calorie-dense foods. It should therefore come as little surprise that robust crosstalk between food and abused substances may be observed in neuronal responses and adaptations, circuits, and even hormonal regulators. Cocaine abuse and addiction is a crushing public health problem that medical approaches have resoundingly failed to address ? new ideas and targets are sorely needed. Our group discovered that a novel gut-based weight-loss surgery (biliary diversion) alters neuronal responses to cocaine, including behavioral measures of cocaine reward. Biliary diversion is capable of chronically elevating circulating bile acids through ligation of the common bile duct and anastomosis of the gallbladder to the ileum (GB-IL). In the control surgery, the gallbladder is anastomosed to the duodenum (GB-D), restoring normal bile flow. Bile acids act as steroid hormones with targets in the brain, including the G protein-coupled bile acid receptor 1 (TGR5) which is expressed in the nucleus accumbens (NAc). Biliary diversion was recently developed at Vanderbilt University to treat high fat diet-induced obesity in mice. GB-IL mice exhibited weight loss and reduced high fat food consumption as compared to GB-D animals. Notably, the weight loss and decreased caloric intake occurred only in animals fed a high fat diet and not in animals fed a regular chow diet. Thus, we hypothesized that this reduction in the intake of rewarding, calorically-dense food could stem, at least in part, from altered reward for palatable food (hedonic eating). Reward is a process regulated by mesolimbic dopamine (DA). Dysregulated mesolimbic DA circuitry has been linked to high fat, high calorie food consumption and, importantly, to cocaine abuse. Thus, understanding how to prevent or correct this dysregulation, is pivotal for developing treatments for cocaine abuse. This proposal stems from the observation that GB-IL, which reduces high fat intake and increases circulating bile acids, also reduces the reinforcing properties of cocaine and impairs the ability of cocaine to enhance released DA. Our overarching hypothesis is that GB-IL and central bile acid signaling regulate cocaine behaviors by impairing cocaine-induced changes in accumbal DA neurotransmission. This hypothesis will be tested within the two Specific Aims below: Aim 1: To determine the neuroadaptations induced by GB-IL and GB-D (control surgery) to accumbal DA homeostasis and to cocaine-induced increase in extracellular DA. Aim 2: To determine the role of GB-IL and central bile acids signaling in modulating cocaine behaviors.